Orally transformable tablets

ABSTRACT

The present invention features a tablet including one or more pharmaceutically active agent(s), one or more thickeners, and one or more binder(s), wherein the tablet includes at least 200 mg of the pharmaceutically active agent(s) and the tablet has been fused with the binder(s) such that the tablet (i) has a water permeation time of less than 60 seconds and (ii) has an in vitro disintegration time of greater than 60 seconds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/887,564, filed Sep. 22, 2010, which claims priority of the benefitsof the filing of U.S. Provisional Application Ser. No. 61/245,315, filedSep. 24, 2009, U.S. Provisional Application Ser. No. 61/255,582, filedOct. 28, 2009, U.S. Provisional Application Ser. No. 61/314,629, filedMar. 17, 2010, and U.S. Provisional Application Ser. No. 61/358,167,filed Jun. 24, 2010. The complete disclosures of the aforementionedrelated U.S. patent applications are hereby incorporated herein byreference for all purposes.

BACKGROUND OF THE INVENTION

Pharmaceuticals intended for oral administration are typically providedin tablet form. Tablets typically are swallowed whole, chewed in themouth, or disintegrated in the oral cavity. Soft tablets that either arechewed or dissolve in the mouth are often employed in the administrationof pharmaceuticals where it is impractical to provide a tablet forswallowing whole often because of the amount of pharmaceutically activeagent to be delivered or for improving compliance of pediatric patients.Many patients, however, do not like chewable tablets. Examples of softtablets designed to disintegrate in the mouth without chewing aredisclosed in U.S. Pat. Nos. 5,464,632, 5,223,264, 5,178,878, 6,589,554,and 6,224,905. However, these technologies are often impractical for usewith tablets containing a large amount of pharmaceutically activeagents, such as acetaminophen which can be dosed at 325 mg or greaterper tablet.

Thus, there is a need for an easy to swallow tablet for delivering largedosages of pharmaceutically active agents. The present invention relatesto the discovery of such a tablet, including the use of such tablets andthe process for making such tablets.

SUMMARY OF THE INVENTION

In one aspect, the present invention features a tablet including one ormore pharmaceutically active agent(s), one or more thickeners, and oneor more binder(s), wherein the tablet includes at least 200 mg of thepharmaceutically active agent(s) and the tablet has been fused with thebinder(s) such that the tablet (i) has a water permeation time of lessthan 60 seconds and (ii) has an in vitro disintegration time of greaterthan 60 seconds.

In another aspect, the present invention features a method ofadministering one or more pharmaceutically active agent(s) by placing asolid tablet including the pharmaceutically active agent(s) into themouth followed by swallowing a liquid, wherein the tablet includes atleast 200 mg of the pharmaceutically active agent(s) and the tablet (i)has a water permeation time of less than 60 seconds and (ii) has an invitro disintegration time of greater than 60 seconds.

In yet another aspect, the present invention features a process formaking a tablet including at one or more pharmaceutically activeagent(s) by the steps of: (a) forming a tablet shape including a powderblend including the pharmaceutically active agent(s) and a binder; and(b) applying energy to the tablet shape for a sufficient period ofactivate the binder within the tablet shape to fuse the tablet shapeinto the tablet, such that the tablet (i) has a water permeation time ofless than 60 seconds and (ii) has an in vitro disintegration time ofgreater than 60 seconds.

Other features and advantages of the present invention will be apparentfrom the detailed description of the invention and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-F are cross-section, side views of an embodiment of theinvention showing the manufacture of tablet 4 a from powder blend 4within die platen 2.

FIGS. 2A-H are cross-section, side views of an embodiment of theinvention showing the manufacture of a bilayer tablet 12 from powderblends 10 and 11 within die platen 2.

FIGS. 3A-G are cross-section, side views of an embodiment of theinvention showing the manufacture of tablet 40 containing preformedinserts 30 and 31 from powder blend 20 within die platen 2.

FIGS. 4A and 4B are a perspective view of a rotary indexing machine 195.

FIGS. 5A and 5B are top views of the rotary indexing machine 195 in thedwell position.

FIGS. 6A and 6B are section views of the lower forming tool assembly 110in the start position of the manufacturing cycle.

FIG. 7 is a section view through the radiofrequency (“RF”) stationrotary indexing machine 195 prior to compacting powder blend 101.

FIG. 8 is a section view through the RF station rotary indexing machine195 prior showing the manufacture of tablets 101 a.

FIG. 9 is a section view through tablet ejection station 160 beforetablets 101 a have been ejected.

FIG. 10 is a section view through tablet ejection station 160 aftertablets 101 a have been ejected into blister 190.

FIGS. 11A-D are cross sections of alternate embodiments of forming toolsand the die platen.

FIGS. 12A-D are cross sections of alternate embodiments of forming toolsand the die platen.

FIG. 13A is a cross section of forming tools having a wave-shapedsurface.

FIG. 13B is a perspective view of forming tools having a wave-shapedsurface.

FIG. 14 is a cross section of forming tools having protrusions at thesurface.

FIG. 15 is a graph depicting the results of a water permeation test.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can, based upon thedescription herein, utilize the present invention to its fullest extent.The following specific embodiments can be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention belongs. Also, all publications, patentapplications, patents, and other references mentioned herein areincorporated by reference. As used herein, all percentages are by weightunless otherwise specified.

As discussed above, in one aspect, the present invention features atablet including one or more pharmaceutically active agent(s), one ormore thickeners, and one or more binder(s), wherein the tablet includesat least 200 mg of the pharmaceutically active agent(s) and the tablethas been fused with the binder(s) such that the tablet (i) has a waterpermeation time of less than 60 seconds and (ii) has an in vitrodisintegration time of greater than 60 seconds. The benefit of such atablet is that it allows for the ease of swallowing of a tablet with alarge amount of pharmaceutically active agent(s). In one embodiment, thetablet transforms from a solid tablet to a formless mass once placed inthe mouth, which formless mass is then more easily swallowed (e.g., witha liquid, such as water).

Powder Blend

As discussed above, the tablet is manufactured by compacting a powderblend containing pharmaceutically active agent(s), binder(s),thickener(s), and optionally a pharmaceutically-acceptable carrier.Examples of binders include but are not limited to meltable binders andwater-activating binding materials. The carrier contains one or moresuitable excipients for the formulation of tablets. Examples of suitableexcipients include, but are not limited to, fillers, adsorbents,disintegrants, lubricants, glidants, sweeteners, superdisintegrants,flavor and aroma agents, antioxidants, preservatives, texture enhancers,and mixtures thereof. One or more of the above ingredients may bepresent on the same particle of the powder blend.

Suitable fillers include, but are not limited to, carbohydrates (asdiscussed herein) and water insoluble plastically deforming materials(e.g., microcrystalline cellulose or other cellulosic derivatives), andmixtures thereof.

Suitable adsorbents include, but are not limited to, water-insolubleadsorbents such as dicalcium phosphate, tricalcium phosphate, silicifiedmicrocrystalline cellulose (e.g., such as distributed under the PROSOLVbrand (PenWest Pharmaceuticals, Patterson, N.Y.)), magnesiumaluminometasilicate (e.g., such as distributed under the NEUSILIN brand(Fuji Chemical Industries (USA) Inc., Robbinsville, N.J.)), clays,silicas, bentonite, zeolites, magnesium silicates, hydrotalcite, veegum,and mixtures thereof.

Suitable disintegrants include, but are not limited to, sodium starchglycolate, cross-linked polyvinylpyrrolidone, cross-linkedcarboxymethylcellulose, starches, microcrystalline cellulose, andmixtures thereof.

Suitable lubricants include, but are not limited to, long chain fattyacids and their salts, such as magnesium stearate and stearic acid,talc, glycerides waxes, and mixtures thereof.

Suitable glidants include, but are not limited to, colloidal silicondioxide. Examples of sweeteners include, but are not limited to,synthetic or natural sugars; artificial sweeteners such as saccharin,sodium saccharin, aspartame, acesulfame, thaumatin, glycyrrhizin,sucralose, dihydrochalcone, alitame, miraculin, monellin, and stevside;sugar alcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol,and xylitol; sugars extracted from sugar cane and sugar beet (sucrose),dextrose (also called glucose), fructose (also called laevulose), andlactose (also called milk sugar); isomalt, salts thereof, and mixturesthereof.

Examples of superdisintegrants include, but are not limited to,croscarmellose sodium, sodium starch glycolate and cross-linked povidone(crospovidone). In one embodiment the tablet contains up to about 5% byweight of such superdisintegrant.

Examples of flavors and aromatics include, but are not limited to,essential oils including distillations, solvent extractions, or coldexpressions of chopped flowers, leaves, peel or pulped whole fruitcontaining mixtures of alcohols, esters, aldehydes and lactones;essences including either diluted solutions of essential oils, ormixtures of synthetic chemicals blended to match the natural flavor ofthe fruit (e.g., strawberry, raspberry and black currant); artificialand natural flavors of brews and liquors, e.g., cognac, whisky, rum,gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint;fruit juices including expelled juice from washed, scrubbed fruits suchas lemon, orange, and lime; spear mint, pepper mint, wintergreen,cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseedsnuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts),almonds, raisins; and powder, flour, or vegetable material partsincluding tobacco plant parts, e.g., genus Nicotiana, in amounts notcontributing significantly to the level of nicotine, and ginger.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.

Examples of preservatives include, but are not limited to, citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid, and mixtures thereof.

Examples of texture enhancers include, but are not limited to, pectin,polyethylene oxide, and carrageenan, and mixtures thereof. In oneembodiment, texture enhancers are used at levels of from about 0.1% toabout 10% percent by weight.

In one embodiment of the invention, the powder blend has an averageparticle size of less than 500 microns, such as from about 50 microns toabout 500 microns, such as from about 50 microns and 300 microns.Particles in this size range are particularly useful for directcompacting processes.

In one embodiment, powder blend/tablet contains less than about 20percent, by weight, of carbohydrates, such as less than about 10percent, by weight, of carbohydrates, such as being substantially freeof a carbohydrate. Examples of carbohydrates include, but are notlimited to, water-soluble compressible carbohydrates such as sugars(e.g., dextrose, sucrose, maltose, isomalt, and lactose), starches(e.g., corn starch), sugar-alcohols (e.g., mannitol, sorbitol, maltitol,erythritol, lactitol, and xylitol), and starch hydrolysates (e.g.,dextrins, and maltodextrins).

In one embodiment, powder blend/tablet is substantially free of directlycompressible water insoluble fillers. Water insoluble fillers includebut are not limited to microcrystalline cellulose, directly compressiblemicrocrystalline cellulose, celluloses, water insoluble celluloses,starch, cornstarch and modified starches. As described in thisembodiment, substantially free is less than 2 percent, e.g. less than 1percent or none.

Meltable Binder

The powder blend/tablet of the present invention includes at least onemeltable binder. In one embodiment, the meltable binder has a meltingpoint of from about 40° C. to about 140° C., such as from about 55° C.to about 100° C. The softening or melting of the meltable binder(s)results in the sintering of the tablet shape through the binding of thesoftened or melted binder with the pharmaceutically active agent and/orother ingredients within the compacted powder blend.

In one embodiment, the meltable binder is a RF-meltable binder. What ismeant by an RF-meltable binder is a solid binder that can be softened ormelted upon exposure to radiofrequency (“RF”) energy. The RF-meltablebinder typically is polar and has the capability to re-harden orresolidify upon cooling.

In one embodiment, the meltable binder is not a RF-meltable binder. Insuch embodiment, the powder blend contains an excipient that heats uponexposure to RF energy (e.g., a polar excipient), such that the resultingheat from is able to soften or melt the meltable binder. Examples ofsuch excipients include, but are not limited to, polar liquids such aswater and glycerin; powdered metals and metal salts such as powderediron, sodium chloride, aluminum hydroxide, and magnesium hydroxide;stearic acid; and sodium stearate.

Examples of suitable meltable binders include: fats such as cocoabutter, hydrogenated vegetable oil such as palm kernel oil, cottonseedoil, sunflower oil, and soybean oil; mono, di, and triglycerides;phospholipids; cetyl alcohol; waxes such as Carnauba wax, spermacetiwax, beeswax, candelilla wax, shellac wax, microcrystalline wax, andparaffin wax; water soluble polymers such as polyethylene glycol,polycaprolactone, GlycoWax-932, lauroyl macrogol-32 glycerides, andstearoyl macrogol-32 glycerides; polyethylene oxides; and sucroseesters.

In one embodiment, the meltable binder is a RF-meltable binder, and theRF-meltable binder is a polyethylene glycol (PEG), such as PEG-4000. Aparticularly preferred RF-meltable binder is PEG having at least 95% byweight of the PEG particles less than 100 microns (as measured byconventional means such as light or laser scattering or sieve analysis)and a molecular weight between 3000 and 8000 Daltons.

The meltable binder(s) may be present at level of about 0.01 percent toabout 50 percent by weight of the powder blend/tablet, such as fromabout 1 percent to about 40 percent, such as from about 5 percent toabout 30 percent of the powder blend/tablet, such as from about 10percent to about 20 percent of the powder blend/tablet. In oneembodiment, the powder blend/tablet contains at least 1 percent byweight, such as at least 5 percent by weight, such as at least 10percent by weight of the powder blend/tablet.

Water-Containing Material

In one embodiment, the powder blend/tablet of the present inventionincludes at least one water-containing material. Examples ofwater-containing materials include, but are not limited to, materialswherein the water is chemically bound to the material (e.g., a hydratesalt), materials wherein the water is adsorbed or absorbed to thematerial (e.g., porous material such a silicas and microsponges), andmaterials that have water encapsulated therein (e.g., liquid filledcapsules). Examples of such materials include, but are not limited to:fumed silicas; colloidal silicas such as colloidal silicon dioxide;silicates such as calcium silicate, aluminum silicate, magnesiumaluminum metasilicate (such as NEUSILIN, US-2 from Fuji Chemical Ltd),and magnesium silicate; clays; zeolites; and veegum.

In one embodiment, the powder blend/tablet contains at least onehydrated salt. Examples of hydrated salts include, but are not limitedto, sodium sulfate hydrate, sodium carbonate hydrate, calcium chloridehydrate, sodium hydrogen phosphate hydrate, and mixtures thereof. In oneembodiment, the hydrated salt has molecular weight from about 150 toabout 400 Daltons, such as from about 200 to about 350 Daltons.

In one embodiment, the powder blend/tablet contains at least one liquidfilled capsule. In a further embodiment, the water is released from thecapsule upon rupture, wherein such rupture is caused by the addition ofenergy.

The water-containing material(s) may be present at level of about 0.01percent to about 70 percent of the powder blend/tablet, such as fromabout 1 percent to about 50 percent, such as from about 1 percent toabout 30 percent, such as from about 2 per cent to about 10 percent ofthe powder blend/tablet.

Water-Activating Binding Material

In one embodiment, the powder blend/tablet of the present inventionincludes at least one water-activating binding material. What is meantby a water-activating binding material is a material that will activateor hydrate upon contact with water (e.g. released from the watercontaining material upon the addition of the energy) and assist inbinding/fusing the powder blend into a tablet. Examples of suchmaterials include, but are not limited to, hydrolyzed proteins,hydrating polymers and hydrocolloids. Suitable hydrolyzed proteinsinclude, but are not limited to, hydrolyzed collagen. Suitable hydratingpolymers include, but are not limited to starches, modified starches,methylcellulose, hydroxypropylcellulose, and hydroxypropylcellulose.Suitable hydrocolloids include, but are not limited to, gelatin, gellangum, carrageenan, and pectin.

Thickener

In one embodiment, the powder blend contains at least one thickener,which allows the tablet to be transformed into a formless mass uponcontact with an aqueous liquid, and which facilitates swallowing.Examples of such thickeners include but are not limited to hydrocolloids(also referred to herein as gelling polymers), gelling starches,crystallizable carbohydrates, and polyethylene oxides. Examples ofsuitable hydrocolloids include, but are not limited to, alginates, agar,guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth,pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan,pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, whelan,rhamsan, zooglan, methylan, chitin, cyclodextrin, and chitosan. Examplesof suitable clays include but are not limited to smectites such asbentonite, kaolin, and laponite, magnesium trisilicate, and magnesiumaluminum silicate. Examples of suitable gelling starches include but arenot limited to acid hydrolyzed starches. Examples of crystallizablecarbohydrates include but are not limited to monosaccharides such asaldohexoses (e.g., the D and L isomers of allose, altrose, glucose,mannose, gulose, idose, galactose, and talose) and the ketohexoses(e.g., the D and L isomers of fructose and sorbose) along with theirhydrogenated analogs (e.g., sorbitol and mannitol).

The thickener may be present at level of about 0.1 percent to about 25percent of the powder blend/tablet, such as from about 2 percent toabout 15 percent or from about 4 percent to about 10 percent of thepowder blend/tablet.

Pharmaceutically Active Agent

The powder blend/tablet of the present invention includes at least onepharmaceutically active agent. What is meant by a “pharmaceuticallyactive agent” is an agent (e.g., a compound) that is permitted orapproved by the U.S. Food and Drug Administration, European MedicinesAgency, or any successor entity thereof, for the oral treatment of acondition or disease. Suitable pharmaceutically active agents include,but are not limited to, analgesics, anti-inflammatory agents,antipyretics, antihistamines, antibiotics (e.g., antibacterial,antiviral, and antifungal agents), antidepressants, antidiabetic agents,antispasmodics, appetite suppressants, bronchodilators, cardiovasculartreating agents (e.g., statins), central nervous system treating agents,cough suppressants, decongestants, diuretics, expectorants,gastrointestinal treating agents, anesthetics, mucolytics, musclerelaxants, osteoporosis treating agents, stimulants, nicotine, andsedatives.

Examples of suitable gastrointestinal treating agents include, but arenot limited to: antacids such as aluminum-containing pharmaceuticallyactive agents (e.g., aluminum carbonate, aluminum hydroxide,dihydroxyaluminum sodium carbonate, and aluminum phosphate),bicarbonate-containing pharmaceutically active agents,bismuth-containing pharmaceutically active agents (e.g., bismuthaluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate,and bismuth subnitrate), calcium-containing pharmaceutically activeagents (e.g., calcium carbonate), glycine, magnesium-containingpharmaceutically active agents (e.g., magaldrate, magnesiumaluminosilicates, magnesium carbonate, magnesium glycinate, magnesiumhydroxide, magnesium oxide, and magnesium trisilicate),phosphate-containing pharmaceutically active agents (e.g., aluminumphosphate and calcium phosphate), potassium-containing pharmaceuticallyactive agents (e.g., potassium bicarbonate), sodium-containingpharmaceutically active agents (e.g., sodium bicarbonate), andsilicates; laxatives such as stool softeners (e.g., docusate) andstimulant laxatives (e.g., bisacodyl); H2 receptor antagonists, such asfamotidine, ranitidine, cimetadine, and nizatidine; proton pumpinhibitors such as omeprazole, dextansoprazole, esomeprazole,pantoprazole, rabeprazole, and lansoprazole; gastrointestinalcytoprotectives, such as sucraflate and misoprostol; gastrointestinalprokinetics such as prucalopride; antibiotics for H. pylori, such asclarithromycin, amoxicillin, tetracycline, and metronidazole;antidiarrheals, such as bismuth subsalicylate, kaolin, diphenoxylate,and loperamide; glycopyrrolate; analgesics, such as mesalamine;antiemetics such as ondansetron, cyclizine, diphenyhydroamine,dimenhydrinate, meclizine, promethazine, and hydroxyzine; probioticbacteria including but not limited to lactobacilli; lactase;racecadotril; and antiflatulents such as polydimethylsiloxanes (e.g.,dimethicone and simethicone, including those disclosed in U.S. Pat. Nos.4,906,478, 5,275,822, and 6,103,260); isomers thereof; andpharmaceutically acceptable salts and prodrugs (e.g., esters) thereof.

Examples of suitable analgesics, anti-inflammatories, and antipyreticsinclude, but are not limited to, non-steroidal anti-inflammatory drugs(NSAIDs) such as propionic acid derivatives (e.g., ibuprofen, naproxen,ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen,fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, and suprofen)and COX inhibitors such as celecoxib; acetaminophen; acetyl salicylicacid; acetic acid derivatives such as indomethacin, diclofenac,sulindac, and tolmetin; fenamic acid derivatives such as mefanamic acid,meclofenamic acid, and flufenamic acid; biphenylcarbodylic acidderivatives such as diflunisal and flufenisal; and oxicams such aspiroxicam, sudoxicam, isoxicam, and meloxicam; isomers thereof; andpharmaceutically acceptable salts and prodrugs thereof.

Examples of antihistamines and decongestants, include, but are notlimited to, bromopheniramine, chlorcyclizine, dexbrompheniramine,bromhexane, phenindamine, pheniramine, pyrilamine, thonzylamine,pripolidine, ephedrine, phenylephrine, pseudoephedrine,phenylpropanolamine, chlorpheniramine, dextromethorphan,diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine,naphazoline, oxymetazoline, montelukast, propylhexadrine, triprolidine,clemastine, acrivastine, promethazine, oxomemazine, mequitazine,buclizine, bromhexine, ketotifen, terfenadine, ebastine, oxatamide,xylomeazoline, loratadine, desloratadine, and cetirizine; isomersthereof; and pharmaceutically acceptable salts and esters thereof.

Examples of cough suppressants and expectorants include, but are notlimited to, diphenhydramine, dextromethorphan, noscapine, clophedianol,menthol, benzonatate, ethylmorphone, codeine, acetylcysteine,carbocisteine, ambroxol, belladona alkaloids, sobrenol, guaiacol, andguaifenesin; isomers thereof; and pharmaceutically acceptable salts andprodrugs thereof.

Examples of muscle relaxants include, but are not limited to,cyclobenzaprine and chlorzoxazone metaxalone, orphenadrine, andmethocarbamol; isomers thereof; and pharmaceutically acceptable saltsand prodrugs thereof.

Examples of stimulants include, but are not limited to, caffeine.

Examples of sedatives include, but are not limited to sleep aids such asantihistamines (e.g., diphenhydramine), eszopiclone, and zolpidem, andpharmaceutically acceptable salts and prodrugs thereof.

Examples of appetite suppressants include, but are not limited to,phenylpropanolamine, phentermine, and diethylcathinone, andpharmaceutically acceptable salts and prodrugs thereof.

Examples of anesthetics (e.g., for the treatment of sore throat)include, but are not limited to dyclonine, benzocaine, and pectin andpharmaceutically acceptable salts and prodrugs thereof.

Examples of suitable statins include but are not limited to atorvastin,rosuvastatin, fluvastatin, lovastatin, simvustatin, atorvastatin,pravastatin and pharmaceutically acceptable salts and prodrugs thereof.

In one embodiment, the pharmaceutically active agent included within thetablet is selected from acetaminophen, antacids, a vitamin, metformin,and pharmaceutically acceptable salts thereof.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of pharmaceutically acceptablesalts, such as acidic/anionic or basic/cationic salts. Pharmaceuticallyacceptable acidic/anionic salts include, and are not limited to acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate and triethiodide. Pharmaceutically acceptablebasic/cationic salts include, and are not limited to aluminum,benzathine, calcium, chloroprocaine, choline, diethanolamine,ethylenediamine, lithium, magnesium, meglumine, potassium, procaine,sodium and zinc.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of prodrugs of thepharmaceutically active agents. In general, such prodrugs will befunctional derivatives of the pharmaceutically active agent, which arereadily convertible in vivo into the required pharmaceutically activeagent. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, theinvention provides the esters, amides, and other protected orderivatized forms of the described compounds.

Where the pharmaceutically active agents according to this inventionhave at least one chiral center, they may accordingly exist asenantiomers. Where the pharmaceutically active agents possess two ormore chiral centers, they may additionally exist as diastereomers. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention. Furthermore, someof the crystalline forms for the pharmaceutically active agents mayexist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the pharmaceutically activeagents may form solvates with water (e.g., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention.

In one embodiment, the pharmaceutically active agent or agents arepresent in the tablet in a therapeutically effective amount, which is anamount that produces the desired therapeutic response upon oraladministration and can be readily determined by one skilled in the art.In determining such amounts, the particular pharmaceutically activeagent being administered, the bioavailability characteristics of thepharmaceutically active agent, the dose regime, the age and weight ofthe patient, and other factors must be considered, as known in the art.

The pharmaceutically active agent may be present in various forms. Forexample, the pharmaceutically active agent may be dispersed at themolecular level, e.g. melted, within the tablet, or may be in the formof particles, which in turn may be coated or uncoated. If thepharmaceutically active agent is in form of particles, the particles(whether coated or uncoated) typically have an average particle size offrom about 1 to about 2000 microns. In one embodiment, such particlesare crystals having an average particle size of from about 1 to about300 microns. In another embodiment, the particles are granules orpellets having an average particle size of from about 50 to about 2000microns, such as from about 50 to about 1000 microns, such as from about100 to about 800 microns.

The pharmaceutically active agent may be present in pure crystal form orin a granulated form prior to the addition of the taste masking coating.Granulation techniques may be used to improve the flow characteristicsor particle size of the pharmaceutically active agents to make it moresuitable for compaction or subsequent coating. Suitable binders formaking the granulation include but are not limited to starch,polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose,and hydroxypropylcellulose. The particles including pharmaceuticallyactive agent(s) may be made by cogranulating the pharmaceutically activeagent(s) with suitable substrate particles via any of the granulationmethods known in the art. Examples of such granulation method include,but are not limited to, high sheer wet granulation and fluid bedgranulation such as rotary fluid bed granulation.

As the dosage form is intended to be swallowed without chewing, in oneembodiment, he pharmaceutically active agent may be present in the formof an uncoated particle (e.g., in crystal form). The use of an uncoatedparticle has the benefit of reducing cost associated with thepharmaceutically active agent and size of the particle (e.g.,grittiness).

If the pharmaceutically active agent has an objectionable taste, thepharmaceutically active agent may be coated with a taste maskingcoating, as known in the art. Examples of suitable taste maskingcoatings are described in U.S. Pat. No. 4,851,226, U.S. Pat. No.5,075,114, and U.S. Pat. No. 5,489,436. Commercially available tastemasked pharmaceutically active agents may also be employed. For example,acetaminophen particles, which are encapsulated with ethylcellulose orother polymers by a coacervation process, may be used in the presentinvention. Coacervation-encapsulated acetaminophen may be purchasedcommercially from Eurand America, Inc. (Vandalia, Ohio) or from CircaInc. (Dayton, Ohio).

In one embodiment, the tablet incorporates modified release coatedparticles (e.g., particles containing at least one pharmaceuticallyactive agent that convey modified release properties of such agent). Asused herein, “modified release” shall apply to the altered release ordissolution of the active agent in a dissolution medium, such asgastrointestinal fluids. Types of modified release include, but are notlimited to, sustained release or delayed release. In general, modifiedrelease tablets are formulated to make the active agents(s) availableover an extended period of time after ingestion, which thereby allowsfor a reduction in dosing frequency compared to the dosing of the sameactive agent(s) in a conventional tablet. Modified release tablets alsopermit the use of active agent combinations wherein the duration of onepharmaceutically active agent may differ from the duration of anotherpharmaceutically active agent. In one embodiment the tablet contains onepharmaceutically active agent that is released in an immediate releasemanner and an additional active agent or a second portion of the sameactive agent as the first that is modified release.

Examples of swellable, erodible hydrophilic materials for use as arelease modifying excipient for use in the modified release coatinginclude water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, and gelling starches. Examples of water swellable cellulosederivatives include sodium carboxymethylcellulose, cross-linkedhydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose. Examplesof polyalkylene glycols include polyethylene glycol. Examples ofsuitable thermoplastic polyalkylene oxides include poly(ethylene oxide).Examples of acrylic polymers include potassiummethacrylatedivinylbenzene copolymer, polymethylmethacrylate, andhigh-molecular weight cross-linked acrylic acid homopolymers andcopolymers.

Suitable pH-dependent polymers for use as release-modifying excipientsfor use in the modified release coating include: enteric cellulosederivatives such as hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, and cellulose acetatephthalate; natural resins such as shellac and zein; enteric acetatederivatives such as polyvinylacetate phthalate, cellulose acetatephthalate, and acetaldehyde dimethylcellulose acetate; and entericacrylate derivatives such as for example polymethacrylate-based polymerssuch as poly(methacrylic acid, methyl methacrylate) 1:2 (available fromRohm Pharma GmbH under the tradename EUDRAGIT S) and poly(methacrylicacid, methyl methacrylate) 1:1 (available from Rohm Pharma GmbH underthe tradename EUDRAGIT L).

In one embodiment the pharmaceutically active agent is coated with acombination of a water insoluble film forming polymer (such as but notlimited to cellulose acetate or ethylcellulose) and a water solublepolymer (such as but not limited to povidone, polymethacrylicco-polymers such as those sold under the tradename Eudragit E-100 fromRohm America, and hydroxypropylcellulose). In this embodiment, the ratioof water insoluble film forming polymer to water soluble polymer is fromabout 50 to about 95 percent of water insoluble polymer and from about 5to about 50 percent of water soluble polymer, and the weight percent ofthe coating by weight of the coated taste-masked particle is from about5 percent to about 40 percent. In one embodiment, the coating which isused in the coated particle of the pharmaceutically active agent issubstantially free of a material (such as polyethylene glycol) whichmelts below 85° C., in order to prevent damage to the integrity of thecoating during the heating step.

In one embodiment, one or more pharmaceutically active agents or aportion of the pharmaceutically active agent may be bound to an ionexchange resin for the purposes of taste-masking the pharmaceuticallyactive agent or delivering the active in a modified release manner.

The susceptibility to energy of the pharmaceutically active agent (e.g.,to melt or degrade) can have an impact on the type of energy and/ortemperature used during the heating step as well as the type of thebinder used.

In one embodiment, the processing of the tablet is free of a wet or hotmelt granulation step. In this embodiment, the materials are directlyblended prior to the addition of heat. In one embodiment, the materialsare directly blended and compressed prior to the addition of heat.

In one embodiment, the tablet contains at least 200 mg of one or morepharmaceutically active agent(s) (i.e., the combined weight of thepharmaceutically active agent(s) in the tablet), such as at least 300 mgof one or more pharmaceutically active agent(s), such as at least 500 mgof one or more pharmaceutically active agent(s), such as at least 1000mg of one or more pharmaceutically active agent(s). In one embodiment,the pharmaceutically active agent(s) is present at level of at leastabout 25 percent by weight of the powder blend/tablet, such as at leastabout 50 percent by weight of the powder blend/tablet, such as at leastabout 75 percent by weight of the powder blend/tablet.

In one embodiment, the pharmaceutically active agent is capable ofdissolution upon contact with a fluid such as water, stomach acid,intestinal fluid or the like. In one embodiment, the dissolutioncharacteristics of the pharmaceutically active agent within the tabletmeets USP specifications for immediate release tablets including thepharmaceutically active agent. For example, for acetaminophen tablets,USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2(paddles) at 50 rpm, at least 80% of the acetaminophen contained in thetablet is released there from within 30 minutes after dosing, and foribuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer,using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofencontained in the tablet is released there from within 60 minutes afterdosing. See USP 24, 2000 Version, 19-20 and 856 (1999). In anotherembodiment, the dissolution characteristics of the pharmaceuticallyactive agent are modified: e.g. controlled, sustained, extended,retarded, prolonged, delayed and the like.

In one embodiment, the particle size of the pharmaceutically activeagent causes more void spaces to be present in the tablet, wherein ahigher particle size of the pharmaceutically active agent subsequentlyrequires a lower level of meltable binder. In one embodiment, whereinthe pharmaceutically active agent or coated pharmaceutically activeagent(s) is greater than 50% of the blend by weight of the powderblend/tablet and the mean particle size of the carbohydrate is greaterthan 100 microns, the meltable binder is from about 10 to about 30percent by weight of the powder blend/tablet. In one embodiment, whereinthe mean particle size of the powder blend is between about 100 micronsand about 300 microns, then meltable binder is from about 10 to about 20percent by weight of the powder blend/tablet.

The melting point of the pharmaceutically active agent can have animpact on the temperature used during the heating step and the type ofmeltable binder used. In one embodiment, the melting point of themeltable binder is less than the melting point of the pharmaceuticallyactive agent. In another embodiment, the melting point of thepharmaceutically active agent is the same or lower than the meltingpoint of the meltable binder, in which case during the fusing or heatingstep, both the pharmaceutically active agent and the meltable binder maymelt and create a eutectic or various bridges of the pharmaceuticallyactive agent and meltable binder between the other materials in thetablet form upon cooling. In one embodiment, the heating temperature isabove the melting point of the meltable binder and below the meltingpoint of the pharmaceutically active agent. In one embodiment whereinibuprofen is the pharmaceutically active agent, the meltable binder isheated from about 30° C. to about 60° C. In one embodiment, thepharmaceutically active agent is the meltable binder.

In one embodiment, the pharmaceutically active agent is in the form of aparticle that is coated with the binder. Examples of such binder coatedparticles include, but are not limited to, meltable materials such asglyceryl palmitostearate.

Manufacture of Tablet Shape

In one embodiment, the tablet shape is pre-formed by light compaction.In one embodiment, the powder blend is fed into the tablet die of anapparatus that applies pressure to form the tablet shape (e.g., by lightcompaction such as tamping). Any suitable compacting apparatus may beused, including, but not limited to, a conventional unitary or rotarytablet press. In one embodiment, the tablet shape may be formed bycompaction using a rotary tablet press (e.g., such as those commerciallyavailable from Fette America Inc., Rockaway, N.J. or Manesty MachinesLTD, Liverpool, UK). In one embodiment, the tablet shape is heated afterit is removed from the tablet press. In another embodiment, the tabletshape is heated within the tablet press.

In one embodiment, to obtain desired attribute of an orallytransformable tablet, the tablet's construction may be highly porous,use a minimal amount of binder, and/or have a low density (e.g., toallow the tablet to collapse in the oral cavity). Such tablets,therefore, are somewhat fragile and soft. In a preferred embodiment, aminimum of tamping/compaction force is desired to achieve the orallytransformable property (low density). Experiments have determined thatlow force compaction without application of energy produced very fragiletablets that could not withstand the forces of material handlingrequired in manufacturing.

In most thermodynamic processes or machines, the heat source and theheat sink are two distinct machines or steps requiring material to betransferred from one apparatus to the other. In the manufacture of thetablets of the present invention, the energy must be added to the tabletto achieve the binding effect and then must be removed from the productto solidify and strengthen it for its final handling packaging and use.One of the unique and unanticipated attributes of one embodiment of themanufacturing process of the present invention is that heat source andheat sink are part of the same apparatus. In fact in early experimentsthe metallic forming tool (e.g., a die punch) which was at roomtemperature removed so much heat from the treated tablet shape (due toits high thermal conductivity) that the surface of the resulting tabletwas unacceptable due to the fact that uniform melting within the powderblend had not taken place. The resulting tablet had a well formed core,but the surface was loose unbound and poorly formed powder that did notadhere to the rest of the tablet. To correct for this thermal loss, inone embodiment, heat was added to the forming tools to achieve propersintering at the surface as well as at the center of the tablet.

To exploit this unique thermal effect, powder blends can also be chosenfor their thermal properties and thermal conductivity and specific heatsuch that the powder blend particles themselves become heat sinks. Thedesirable result of this is that the total process time can be just afew seconds and that the tablet does not need to be transferred from thedie platen during the critical tamping and heating process. The dieplaten can function then as a material handling apparatus as well as athermal forming tool. This is particularly advantageous for successfulmanufacture of fragile orally transformable tablets.

In one embodiment, the compaction step (e.g., tamping) which occursprior to the addition of the energy utilizes a compaction force which isless than the force required to compress a chewable or swallowabletablet. In one embodiment, the compaction force is less than about 1000pounds per square inch (e.g., less than about 500 pounds per squareinch, such as less than 200 pounds per square inch, such as less than 50pounds per square inch). In one embodiment, the energy is applied whilethe powder blend is under such force.

In one embodiment, the compaction step occurs in an indexed manner,where one set of tablets are compacted simultaneously, before rotatingto another indexing station. In one embodiment, the compaction stepoccurs at a single indexing station and the application of energy occursat a separate indexing station. In another embodiment, a third indexingstation is present wherein the ejection of the tablet or multipletablets occurs, wherein the lower forming tool is raised up through andup to the surface of the die. In another embodiment the compaction stepis performed through the addition of air pressure or hydraulic cylinderto the top of the upper forming tools. In one embodiment multipletablets are ejected simultaneously and separated from the surface of theindexing station and removed via a take-off bar.

In another embodiment, the tablet shape may be prepared by thecompaction methods and apparatus described in United States PatentApplication Publication No. 20040156902. Specifically, the tablet shapemay be made using a rotary compression module including a fill zone,insertion zone, compression zone, ejection zone, and purge zone in asingle apparatus having a double row die construction. The dies of thecompression module may then be filled using the assistance of a vacuum,with filters located in or near each die. The purge zone of thecompression module includes an optional powder blend recovery system torecover excess powder blend from the filters and return the powder blendto the dies. In one embodiment the energy source (e.g., RF energysource) is projected through the die table of a rotary press into theappropriate electrode within the forming tool or the forming cavity. Inone embodiment the die table is constructed of non-conductive material.

In another embodiment, a portion of the tablet shape may be prepared bya wet-granulation method, in which the excipients and a solution ordispersion of a wet binder (e.g., an aqueous cooked starch paste orsolution of polyvinyl pyrrolidone) are mixed and granulated. Suitableapparatus for wet granulation include low shear mixers (e.g., planetarymixers), high shear mixers, and fluid beds (including rotary fluidbeds). The resulting granulated material may then be dried, andoptionally dry-blended with further ingredients (e.g., excipients suchas, for example, the binders described in the invention herein,lubricants, colorants, and the like). The final dry blend is thensuitable for compaction by the methods described herein. Methods fordirect compaction and wet granulation processes are known in the art.

In one embodiment, the tablet shape is prepared by the compactionmethods and apparatus described in issued U.S. Pat. No. 6,767,200.Specifically, the tablet shape is made using a rotary compression moduleincluding a fill zone, compression zone, and ejection zone in a singleapparatus having a double row die construction as shown in FIG. 6therein. The dies of the compression module are preferably filled usingthe assistance of a vacuum, with filters located in or near each die.

The tablet shape may have one of a variety of different shapes. Forexample, the tablet shape may be shaped as a polyhedron, such as a cube,pyramid, prism, or the like; or may have the geometry of a space figurewith some non-flat faces, such as a cone, truncated cone, triangle,cylinder, sphere, torus, or the like. In certain embodiments, a tabletshape has one or more major faces. For example, the tablet shape surfacetypically has opposing upper and lower faces formed by contact with theupper and lower forming tool faces (e.g., die punches) in the compactionmachine. In such embodiments, the tablet shape surface typically furtherincludes a “belly-band” located between the upper and lower faces, andformed by contact with the die walls in the compaction machine. A tabletshape/tablet may also be a multilayer. Applicants have found that sharpedges in the tooling used to make the tablets can cause arcing, and thusmore rounded edges may be needed.

In one embodiment, the method of producing the tablet shape issubstantially free of the use of solvents. In this embodiment, thepowder blend is substantially free of solvents, and the manufacturingprocess (e.g., filling process into the die) is also substantially freeof solvents. Solvents may include, but are not limited to, water,organic solvents such as but not limited to alcohols, chlorinatedsolvents, hexanes, or acetone; or gaseous solvents such as but notlimited to nitrogen, carbon dioxide or supercritical fluids.

In one embodiment a vibratory step is utilized (e.g., added afterfilling of the powder blend but prior to the heating or fusing step, inorder to remove air from the powder blend). In one embodiment avibration with the frequency from about 1 Hz to about 50 KHz is addedwith amplitude from 1 micron to 5 mm peak-to-peak to allow for theflowable powder blend to settle into the cavity of a the die platen(“forming cavity”).

In one embodiment, as shown in FIGS. 1A-1F, a metered volume of powderblend 4 is filled into a Teflon® (or similar electrical and RF energyinsulative material such as ceramic or UHMW plastic) die platen 2. Dieplaten 2 has forming cavity 5 with inner wall 6, upper opening 7 on theupper surface of die platen 2 (which allows powder blend 4 and upperforming tool 1 to move into the forming cavity 5), and lower opening 8on the opposite surface of die platen 2 (which allows powder blend 4 andlower forming tool 3 to move into the forming cavity 5). Powder blend 4may be either gravity fed or mechanically fed from a feeder (not shown).A metallic, electrically conductive lower forming tool 3 is insertedinto the die platen to retain the powder blend 4, within die platen 2. Asimilar metallic, electrically conductive upper forming tool 1 ispositioned above the die platen 2 as shown in FIG. 1B. The forming tools1 and 3, die platen 2, and powder blend 4 are then moved to a compactionand RF heating station as shown in FIG. 1C to form tablet shape 4 a.

This heating station is comprised of an RF generator 7 which producesthe necessary high voltage, high frequency energy. The generator 7 iselectrically connected to movable upper RF electrode plate 8 and movablelower RF electrode plate 6. As shown in FIG. 1C, at this position, thepowder blend 4 is compacted between an upper forming tool 1 and a lowerforming tool 3 by pressure exerted by upper RF electrode plate 8 andlower electrode plate 6 to form tablet shape 4 a. Tablet shape 4 a isthen exposed to RF energy from RF generator 7, which heats the meltablebinder within tablet shape 4 a. After the RF energy is switched off,tablet shape 4 a cools to form the tablet 4 b. In one embodiment, asshown in FIG. 1D, tablet 4 b is pushed by upper forming tool 1 from thedie platen 2 into blister 8, which is used to package tablet 4 b. In analternative embodiment, as shown in FIG. 1E, tablet 4 b is pushed fromthe die platen 2 by the lower forming tool 3 and guided to an ejectionchute by a stationary “take-off” bar (not shown). FIG. 1F shows a 3dimensional representation of the forming tools 1 and 4, die platen 2,and tablet 4 b.

In FIGS. 2A-2H, an alternate embodiment of the invention is shown wherea multilayer tablet is produced. First, powder blend 10 is filled intodie platen 2 as shown in FIG. 2A. Powder blend 10 is tamped or moveddown into die platen 2 by upper forming tool 1 as shown in FIG. 2B toform tablet shape 10 a. Then, powder blend 11 is then filled on top oftablet shape 10 a. The forming tools 1 and 3, die platen 2, tablet shape10 a and powder blend 11 are then moved to the compaction and RF heatingstation as shown in FIG. 2E. RF heating is accomplished as describedabove in FIG. 1C to produce multilayer tablet 12 as shown in FIGS. 2Fand 2G. While a bi-layer tablet is shown in the drawing, additionalmultiple layers can be produced by adding additional powder blends todie platen 2.

FIGS. 3A-3G show another embodiment of the invention where preformedinserts 30 and 31 are inserted into tablet shape 20 a as shown in FIGS.3A-3D. Forming tools 1 and 3, die platen 2, tablet shape 20, andpreformed inserts 30 and 31 are then moved to the compaction and RFheating station as shown in FIG. 3E. RF heating is accomplished asdescribed above in FIG. 1C to produce a multi-component tablet 40 shownin FIGS. 2F and 2G.

FIGS. 4A and 4B show two views of a rotary indexing machine 195 which isdesigned to create large quantities of tablets. In particular, theconfiguration of the apparatus shown is designed to manufacture fragiletablets with minimized risk of damaging them as they are moved throughthe various manufacturing steps. This embodiment of the invention iscomprised of an indexing table 170 having four sets of die platens 175each having sixteen cavities, powder feeder 100, RF generator 150, amachine frame 140, moving RF electrode assemblies 120 and 130, lowerforming tool assembly 110, upper forming tool assembly 210, tabletejection station 160, indexer drive system 180, blister package web 190,and blister lid material roll 191.

FIG. 5A is a top view of the apparatus in the dwell position. FIG. 5B isa top view of the apparatus as the indexing table 170 rotates betweenstations in direction “A”. FIG. 6A depicts a section view through thelower forming tool assembly 110 in a start position of the manufacturingcycle. The lower forming tools 111, which are made of an electricallyconductive metallic material such as brass or stainless steel, areretained in retainer plate 112 (e.g., made of aluminum or steel). Heatedblock 117 is attached to the retainer plate 112 and contains fluidpassages 117 b. Heated (or optionally cooling) fluid is circulatedthrough the heated block 117 by connections to flexible hoses 119 a and119 b which form a supply and return circuit. Heating can also beaccomplished by electric cartridge heaters or other suitable means (notshown). Attached to the retainer plate are cam-follower 114 and linearbearing 113. A guide shaft 116 is fixed to indexing table 170. Theretainer plate and forming tools 111 and are moveable up or downaccording to the profile of barrel cam 115 which cam follower 114 rollsupon. Also shown is die platen 171, which is made of electrical and RFenergy insulative material such as Teflon, UHMW, or ceramic. This isnecessary to prevent a short circuit when the electrically conductiveforming tools are positioned in the RF electric field in subsequentsteps. The forming cavity 171 a is shown empty at this stage of theprocess.

FIG. 6B depicts a section through the powder feeder station 100 of theapparatus. In this station powdered powder blend 101 is gravity fed intodie platen 171. Movable cam segment 118 is adjusted up or down indirection “B” to vary the volume of the forming cavity 171 a by changingthe amount that the lower forming tools 111 penetrate into the dieplaten 171. This adjustable volume feature enables the precise dose ofpowdered powder blend to be selected for a desired tablet weight. Whenthe machine indexes out of the powder feeder station, the rim of feeder102 scrapes against the die platen 171 to create a level powder surfacerelative to the surface of the die platen 171.

FIG. 7 is a section view through the RF station of the apparatus. The RFgenerator 150 is depicted symbolically here. In one embodiment, theconfiguration of the RF generator 150 is a free running oscillatorsystem. It is typically composed of a power vacuum tube (such as atriode), a DC voltage source between 1000 and 8000 volts connectedacross the cathode and plate (anode). A tank circuit is used to impose asinusoidal signal upon the control grid and electrodes thereby producingthe necessary frequency (typically 13.56 MHZ or 27.12 MHZ) and highvoltage field. An example of such RF generator 150 is the COSMOS ModelC10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, N.Y.). Inanother embodiment, RF energy can be provided by a 50 Ohm systemcomposed of a waveform generator which feeds a radio frequency signal topower amplifiers which are coupled to the electrodes and the load by animpedance matching network.

In FIG. 7, a lower movable RF electrode 121 is shown, movable indirection “D”. It is represented in its down position. The linearmovement is generated by linear actuators which are typically devisessuch as air cylinders or servo motors. Two air cylinders are depicted inFIG. 7. Air cylinder bodies 141 and 142 apply pressure to guide rods 144and 143. Moving platens 132 and 122 are connected to the guide rods andprovide an electrically isolated mounting for electrode plates 131 and121. RF generator 150 connects to the electrode plates 131 and 121through wires 185 and 184. A movable upper RF electrode assembly 130,movable in direction “C”, is shown in its up position. Upper formingtools 133, retainer plate 134, and heated block 135 are all attached tothe movable RF electrode plate 131 and, consequently, move up and downwith it. Powder blend 101 is within die platen 171.

FIG. 8 is a section through the same RF station but shows the RFelectrodes 131 and 121 pressing against the respective forming toolassemblies 133 and 111 to both compact and apply RF energy to powderblend 101 creating tablet 101 a. After application of the RF energy isstopped, the moveable RF electrode plates refract, and the indexingplate 170, die platen 171, and lower forming tool assembly 110 areindexed to the next station.

FIG. 9 is a section view through the tablet ejection station 160.Ejector pins 161 are attached to movable plate 162 (movable in the “E”direction), which is actuated by actuator assembly 163 (for example,this can be a linear servo motor or air cylinder or other suitableactuator). Actuator rod 166 connects to the movable plate 162. Linearbearing 164 and guide rod 165 provide rigidity and support for theactuator plate 162 and prevent destructive side loads created by theejection force from acting upon actuator 163. A blister package 190 isshown below die platen 171.

FIG. 10 is a section through the same assembly after the ejector pins161 have pushed finished tablets 101 a through the die platen 171. Thisdirect placement of tablet into blister helps prevent breakage thatcould occur while using typical means such as feeders or by dumpingtablets into transport drums.

In one embodiment, a lubricant is added to forming cavity prior to theaddition of the flowable powder blend. This lubricant may be a liquid orsolid. Suitable lubricants include but are not limited to solidlubricants such as magnesium stearate, starch, calcium stearate,aluminum stearate and stearic acid; or liquid lubricants such as but notlimited to simethicone, lecithin, vegetable oil, olive oil, or mineraloil. In certain embodiments, the lubricant is added at a percentage byweight of the tablet of less than 5 percent, e.g. less than 2 percent,e.g. less than 0.5 percent. In certain embodiments, the presence of ahydrophobic lubricant can disadvantageously compromise thedisintegration or dissolution properties of a tablet. In one embodimentthe tablet is substantially free of a hydrophobic lubricant. Hydrophobiclubricants include magnesium stearate, calcium stearate and aluminumstearate.

Heating of Tablet Shape to Form Tablet

Various forms of energy may be used in the process to activate thebinder. Suitable sources of energy include but are not limited toconvection, radio frequency, microwave, UV light, infrared, induction,laser light, and ultrasonic sound.

In one embodiment, radiofrequency energy is used. Radiofrequency heatinggenerally refers to heating with electromagnetic field at frequenciesfrom about 1 MHz to about 100 MHz. In one embodiment of the presentinvention, the RF-energy is within the range of frequencies from about 1MHz to about 100 MHz (e.g., from about 5 MHz to 50 MHz, such as fromabout 10 MHz to about 30 MHz). RF energy generators are well known inthe art. Examples of suitable RF generators include, but are not limitedto, COSMOS Model C10X16G4 (Cosmos Electronic Machine Corporation,Farmingdale, N.Y.).

The energy (e.g., RF energy) is used to activate the binder. The degreeof compaction, the type and amount of binder, and the amount of energyused can determine the hardness and/or type of tablet.

In one embodiment when RF energy is used, the upper and lower formingtools serve as the electrodes (e.g., they are operably associated withthe RF energy source) through which the RF energy is delivered to thetablet shape. In one embodiment, there is direct contact between atleast one RF electrode (e.g., forming tool) and the tablet shape. Inanother embodiment, there is no contact between any of the RF electrode(e.g., forming tools) and the tablet shape. In one embodiment, the RFelectrodes are in direct contact with the surface of the tablet shapewhen the RF energy is added. In another embodiment, the RF electrodesare not in contact (e.g., from about 1 mm to about 1 cm from the surfaceof the tablet shape) during the addition of the RF energy.

In one embodiment, the RF energy is delivered while the tablet shape isbeing formed. In one embodiment, the RF energy is delivered once thetablet shape is formed. In one embodiment, the RF energy is deliveredafter the tablet shape has been removed from the die.

In one embodiment, the RF energy is applied for a sufficient time tosoften and melt substantially all (e.g., at least 90%, such as at least95%, such as all) of the binder within the tablet shape. In oneembodiment, the RF energy is applied for a sufficient time to soften andmelt only a portion (e.g., less than 75%, such as less than 50%, such asless than 25%) of the binder within the tablet shape, for example onlyon a portion of the tablet shape, such as the outside of the tabletshape.

In alternate embodiments of the invention, the forming tools can beconstructed to achieve localized heating effects and can also beconfigured to shape the electric field that is developed across thetools. FIG. 11A shows one such configuration. An RF generator 200 isconnected to RF electrode plates 201 and 202. Forming tools 205 and 204are constructed of an electrically conductive material and they have anattachment 207 and 208 which are made of electrical and RF energyinsulative material such as ceramic, Teflon®, polyethylene, or highdensity polyethylene. Die platen 203 is also constructed of electricaland RF energy insulative material. This configuration creates greaterdistance between the conductive forming tools to weaken the electricfield which is beneficial for producing thin tablets without the risk ofan electric arc forming which would damage the product and tooling. FIG.11B depicts a similar configuration but with forming tools 210 and 211that, respectively, have a recess containing insert 213 and 212 whichare made of electrical and RF energy insulative material. This geometrywill produce a tablet with lesser heating in the area where the inserts213 and 212 are located since the electric field is weaker due to thegreater distance between the conductive portions of 211 and 210. FIG.11C is similar to FIG. 11B only the geometry is reversed so the tabletformed by this configuration will have a greater heating effect at thecenter since the inserts 216 and 217 are at the periphery of respectiveforming tools 214 and 215. FIG. 11D depicts another embodiment wherebythe die platen is constructed of an electrically conductive component221 and electrically insulating component 222, which is made ofelectrical and RF energy insulative material. Forming tools 219 and 218are electrically conductive, but forming tool 218 further containssecond electrically insulating component 220 around the surface of upperforming tool 218 which contact tablet shape 206. This configurationcreates an electric field and associated zones of heating that ispreferential to the conductive portions of the die platen.

FIG. 12A is similar to FIG. 11D except the die platen 233 in thisembodiment is constructed entirely of electrically conductive material.FIGS. 12B and 12C depict two embodiments where the die platen comprisesa respective center portion 245 and 254 that are electrically conductiveand respective outer portions 244/246 and 252/253 is are made ofelectrical and RF energy insulative material. FIG. 12B further includesinsulating component 220 around the surface of lower forming tool 219.FIG. 12D is a further embodiment where the forming tools 263 and 262 aremade of electrical and RF energy insulative material. The die platenportions 264 and 265 are made of electrical and RF energy insulativematerial, but there are two respective electrically conductive portions267 and 266 which are attached to the RF generator circuit 200. In thisconfiguration, the electric field is applied in the horizontal directionacross the tablet shape 206.

As described above, the distance between conductive portions of theforming tool has a strong effect on field strength and heating effect.To create a tablet with uniform heating and texture, a forming tool thatis constructed with equidistant spacing is desirable. FIGS. 13A and 13Bdepict such a configuration. In this embodiment, a wave-shaped formingtools 270 and 273 are shown to create a tablet 272 within die platen 271with a unique appearance. The profiles of the forming tool surfaces areequidistant as shown by dimension “X”.

FIG. 14 is an embodiment wherein a non-uniform heating is used tomanufacture tablet 282. In this embodiment, a tablet with hard and softzones is created. The forming tools 280 and 281 are made withprotrusions at the surface that create high field strength (resulting ingreater heating) where they are closest together (shown by the dimension“Z”) and weaker field strength (resulting in lesser heating) where theyare further apart (shown by the dimension “Y”).

In one embodiment, to help reduce sticking, the tablet is cooled withinthe forming cavity to cool and/or solidify the binder. The cooling canbe passive cooling (e.g., at room temperature) or active cooling (e.g.,coolant recirculation cooling). When coolant recirculation cooling isused, the coolant can optionally circulate through channels inside theforming tools (e.g., punches or punch platen) and/or die or die platen(e.g., as discussed above in FIGS. 6A and 6B). In one embodiment, theprocess uses a die platen having multiple die cavities and upper andlower punch platens having multiple upper and lower punched forsimultaneous forming of a plurality of tablets wherein the platens areactively cooled.

In one embodiment, there is a single powder blend forming the tabletshape which is then heated with the RF energy. In another embodiment,the tablet is formed of at least two different powder blends, at leastone powder blend being RF-curable and at least one formulation being notRF-curable. When cured with RF energy, such tablet shape develops two ormore dissimilarly cured zones. In one embodiment, the outside area ofthe tablet shape is cured, while the middle of the tablet shape is notcured. By adjusting the focus of the RF heating and shape of the RFelectrodes, the heat delivered to the tablet shape can be focused tocreate customized softer or harder areas on the finished tablet.

In one embodiment the RF energy is combined with a second source of heatincluding but not limited to infrared, induction, or convection heating.In one embodiment, the addition of the second source of heat isparticularly useful with a secondary non-RF-meltable binder present inthe powder blend.

In one embodiment, the powder blend is sealed within a chamber duringthe step with which the energy is applied, so that the water iscontained and can be distributed throughout the powder blend. In oneversion of this embodiment, the sealed chamber consists of a die, and atleast one heat source (e.g., RF applying electrode). In one embodiment,upon opening of the sealed chamber, the fused tablet is further dried inorder to allow for the water to escape. This drying step may be achievedusing the energy source or another source of heat.

In one embodiment, microwave energy is used (e.g., in place ofradiofrequency energy) to manufacture the tablet. Microwave heatinggenerally refers to heating with electromagnetic field at frequenciesfrom about 100 MHz to about 300 GHz. In one embodiment of the presentinvention, the RF-energy is within the range of frequencies from about500 MHz to about 100 GHz (e.g., from about 1 GHz to 50 GHz, such as fromabout 1 GHz to about 10 GHz). The microwave energy is used to heat thebinder (e.g., either directly when the meltable binder is susceptible tomicrowave energy (“microwave meltable binder”) or indirectly when themeltable binder is not a microwave meltable binder but is heated by amicrowave heatable ingredient within the powder blend. In such anembodiment, a microwave energy source and microwave electrodes are usedin the machine used to manufacture the dosage form.

Inserts within Tablet Shape

In one embodiment, an insert is incorporated into the tablet shapebefore the energy is delivered. Examples include solid compressed formsor beads filled with a liquid composition. Such incorporation of aninsert is depicted in FIGS. 3A-3G.

In one embodiment the pharmaceutically active agent is in the form of agel bead, which is liquid filled or semi-solid filled. The gel bead(s)are added as a portion of the powder blend. In one embodiment, thetablet of this invention has the added advantage of not using a strongcompaction step, allowing for the use of liquid or semisolid filledparticles or beads which are deformable since they will not rupturefollowing the reduced pressure compaction step. These bead walls maycontain gelling substances such as: gelatin; gellan gum; xanthan gum;agar; locust bean gum; carrageenan; polymers or polysaccharides such asbut not limited to sodium alginate, calcium alginate, hypromellose,hydroxypropyl cellulose and pullulan; polyethylene oxide; and starches.The bead walls may further contain a plasticizer such as glycerin,polyethylene glycol, propylene glycol, triacetin, triethyl citrate andtributyl citrate. The pharmaceutically active agent may be dissolved,suspended or dispersed in a filler material such as but not limited tohigh fructose corn syrup, sugars, glycerin, polyethylene glycol,propylene glycol, or oils such as but not limited to vegetable oil,olive oil, or mineral oil.

In one embodiment, the insert is substantially free of RF-absorbingingredients, in which case application of the RF energy results in nosignificant heating of the insert itself. In other embodiments, theinsert contains ingredients and are heated upon exposure to RF energyand, thus, such inserts can be used to soften or melt the meltablebinder.

Multi-Layer Tablet

In certain embodiments, the tablet includes at least two layers, e.g.,with different types and/or concentrations of binders and/or otheringredients or different concentrations of pharmaceutically activeagents. Such an embodiment is shown in FIGS. 2A-2D. In one embodiment,the tablet includes two layers, one layer having orally disintegratingproperties and another layer having the disintegration properties uponcontact with water as described in the water permeation test. In oneembodiment, one layer has a binder and another layer does not have abinder. In one embodiment one layer is compacted at higher compactionforce versus the other layer. In one embodiment one layer is compactedand the other layer is formed or shaped by a preform step and then fusedutilizing the thermal methods described herein. In one embodiment, onelayer is fused using one level of thermal energy and a second layer isfused using a second level of thermal energy. In one embodiment, bothlayers contain same amount of the binder, but have different amount ofpharmaceutically active agents and/or other excipients. In oneembodiment, all properties of the two layers are identical but thecolors of the two layers are different.

Effervescent Couple

In one embodiment, the powder blend further contains one or moreeffervescent couples. In one embodiment, effervescent couple containsone member from the group consisting of sodium bicarbonate, potassiumbicarbonate, calcium carbonate, magnesium carbonate, and sodiumcarbonate, and one member selected from the group consisting of citricacid, malic acid, fumaric acid, tartaric acid, phosphoric acid, andalginic acid.

In one embodiment, the combined amount of the effervescent couple(s) inthe powder blend/tablet is from about 2 to about 20 percent by weight,such as from about 2 to about 10 percent by weight of the total weightof the powder blend/tablet.

Hardness/Density of Tablet Shape/Tablet

In one embodiment, the tablet is prepared such that the tablet isrelatively soft (e.g., capable of disintegrating in the mouth or beingchewed). In one embodiment, the hardness of the tablet is preferablyless than about 3 kilopounds per square centimeter (kp/cm²) (e.g., lessthan about 2 kp/cm², such as less than about 1 kp/cm²).

Hardness is a term used in the art to describe the diametral breakingstrength as measured by conventional pharmaceutical hardness testingequipment, such as a Schleuniger Hardness Tester. In order to comparevalues across different size tablets, the breaking strength must benormalized for the area of the break. This normalized value, expressedin kp/cm², is sometimes referred in the art as tablet tensile strength.A general discussion of tablet hardness testing is found in Leiberman etal., Pharmaceutical Dosage Forms—Tablets, Volume 2, 2.sup.nd ed., MarcelDekker Inc., 1990, pp. 213-217, 327-329.

A more preferred test for hardness of the tablet of the presentinvention relies upon a Texture Analyzer TA-XT2i that is fitted with a 7millimeter diameter flat faced probe and setup to measure and reportcompression force in grams. The probe moves at 0.05 millimeters persecond to a depth of penetration of 2 millimeters. The maximumcompression force is recorded. In one embodiment, the measured forcesrecorded for tablets made in accordance with the present invention areless than 10,000 grams (e.g., less than about 1000 grams, such as lessthan about 700 grams. In one embodiment, the measured forces recordedfor tablets made in accordance with the present invention ranges fromabout 100 grams to about 6000 grams, such as from about 100 grams toabout 1000 grams, such as from about 75 grams to about 700 grams) with adeviation of ±50 grams. In another embodiment the measured forcesrecorded for tablets is less than 700 grams.

In one embodiment, the density of the tablet is less than about 2 g/cc(e.g., less than about 0.9 g/cc, such as less than about 0.8 g/cc, suchas less than about 0.7 g/cc). In one embodiment, the difference in thedensity of the powdered material following the compaction step is lessthan about 40 percent (e.g., less than about 25 percent, such as lessthan about 15 percent).

Tablets Coatings

In one embodiment, the tablet includes an additional outer coating(e.g., a translucent coating such as a clear coating) to help limit thefriability of the tablet. Suitable materials for translucent coatingsinclude, but are not limited to, hypromellose, hydroxypropylcellulose,starch, polyvinyl alcohol, polyethylene glycol, polyvinylalcohol andpolyethylene glycol mixtures and copolymers, and mixtures thereof.Tablets of the present invention may include a coating from about 0.05to about 10 percent, or about 0.1 to about 3 percent by weight of thetotal tablet.

Water Permeation Time Test

In one embodiment, the tablet has a water permeation time of less than60 seconds, such as less than 30 seconds, such as less than 15 seconds.What is meant by “water permeation time” is the amount of time it takesfor a 5 millimeter diameter flat faced probe, at 25 grams of force, topenetrate 2 mm through the tablet following immersion of the tabletdeionized water at 25° C. To conduct such test, a texture analyzer, suchas Texture Analyzer TA-XT2i, that is fitted with the 5 millimeterdiameter flat faced probe is used. The texture analyzer is set tomeasure and report the distance in mm that the probe penetrates into thesubmersed tablet. The tablet is placed into a 1oz. plastic cup and theprobe is placed along the longest axis (the circumference). The probe isactivated so that it pushes against the tablet. Ten seconds after theprobe is activated and pushing against the tablet, deionized water at25° C. is added to the cup in an amount to cover the tablet. Thedistance the probe penetrates into the tablet is then recorded overtime. The amount of time it takes for the probe to penetrate 1 mmthrough the tablet is recorded as the water permeation time.

In Vitro Disintegration Test

In one embodiment, the tablet has an in vitro disintegration time ofgreater than 60 seconds, such as greater than 180 seconds, such asgreater than 300 seconds. What is meant by “in vitro disintegrationtime” is the amount of time it takes for the tablet to fullydisintegrate utilizing the disintegration test and apparatus asdescribed in the General Chapter Section 701 of the United StatesPharmacopeia (USP), wherein the disintegration apparatus is fitted witha 10 mesh screen and the disintegration of the tablet is observed inwater at 37° C.

Surface Treating of the Tablet

In one embodiment, the surface of the tablet shape and/or the tablet isfurther treated with energy (e.g., convection, infrared, or RF energy)to soften or melt the material on the surface of the tablet and thencooled or allowed to cool to further smooth the texture, enhance thegloss of surface of the tablet, limit the friability of the tablet,and/or provide a mark for identification. In one embodiment, the surfaceof the tablet is further exposed to infrared energy wherein the majority(at least 50 percent, such as least 90 percent, such as at least 99percent) of the wavelength of such infrared energy is from about 0.5 toabout 5 micrometers such as from about 0.8 to about 3.5 micrometers(e.g., by use of a wavelength filter). In one embodiment, the infraredenergy source is a quartz lamp with a parabolic reflector (e.g., tointensify the energy) and a filter to remove unwanted frequencies.Examples of such infrared energy sources include the SPOT IR 4150(commercially available from Research, Inc., Eden Prairie, Minn.).

Use of Tablet

In one embodiment, the present invention features a method of treatingan ailment, the method including orally administering theabove-described tablet wherein the tablet includes an amount of thepharmaceutically active agent effective to treat the ailment. Examplesof such ailments include, but are not limited to, pain (such asheadaches, migraines, sore throat, cramps, back aches and muscle aches),fever, inflammation, upper respiratory disorders (such as cough andcongestion), infections (such as bacterial and viral infections),depression, diabetes, obesity, cardiovascular disorders (such as highcholesterol, triglycerides, and blood pressure), gastrointestinaldisorders (such as nausea, diarrhea, irritable bowel syndrome and gas),sleep disorders, osteoporosis, and nicotine dependence.

In one embodiment, the method is for the treatment of an upperrespiratory disorder, wherein the pharmaceutically active agent isselected from the group of phenylephrine, cetirizine, loratadine,fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine,chlophedianol, and pseudoephedrine.

In this embodiment, the “unit dose” is typically accompanied by dosingdirections, which instruct the patient to take an amount of thepharmaceutically active agent that may be a multiple of the unit dosedepending on, e.g., the age or weight of the patient. Typically the unitdose volume will contain an amount of pharmaceutically active agent thatis therapeutically effective for the smallest patient. For example,suitable unit dose volumes may include one tablet.

In one embodiment, the solid tablet is designed to collapse to form asemi-solid mass upon administration in the mouth. This mass is thenswallowed with the assistance of a aqueous liquid such as water. Asbeing a semisolid, it is much easier to swallow than a hard tablet. Inone embodiment, the volume of the semisolid mass is not more than 10times the volume of the tablet prior to placement into an aqueous liquidat 37° C. at 60 seconds.

EXAMPLES

Specific embodiments of the present invention are illustrated by way ofthe following examples. This invention is not confined to the specificlimitations set forth in these examples.

Example 1 Preparation of Tablet Containing Acetaminophen

The tablet shapes of Table 1 were prepared as follows. The sucralose,peppermint flavor and tapioca maltodextrin were manually passed througha 50 mesh screen. The acetaminophen (APAP) granular, polyethylene glycol(PEG), and polyethylene oxide (PEO) were added to the above mixture in aplastic bottle, mixed end-over end for approximately three minutes, andthen discharged. The blend was then individually dosed into a simulatedcapsule-like medicament (“caplet”) die utilizing 624 mg of the blend pertablet. The tablet shapes were then heated using convection heat to fusethe granulation into a unified tablet.

TABLE 1 APAP 500 mg Tablet Shape Formulation Material G/Batch mg/tabWeight % Sucralose 0.64 4.0 0.64 Peppermint Flavor¹ 1.60 10.0 1.60 APAPGranular² (uncoated 80.13 500.0 80.13 granulation) Polyglykol 4000³(Polyethylene 7.21 50.0 7.21 Glycol) Polyethylene Oxide (Grade WSR 303)⁴5.61 35.0 5.61 Tapioca Maltodextrin (N-Zorbit M⁵) 4.81 30.0 4.81 TOTAL100.0 629.0 100.0 ¹Commercially available from Virginia Dare inBrooklyn, NY ²Commercially available from Mallinckrodt Corporation inHazelwood, MO ³Commercially available from Clariant PF in Rothausstr,Switzerland ⁴Commercially available from the DOW Corporation in Midland,MI ⁵Commercially available from National Starch in Bridgewater, NJ

Example 2 Preparation of Tablets Containing Acetaminophen

The following tablets in Table 2 containing APAP were made in the samemanner as in Example 1.

TABLE 2 APAP 500 mg Tablet Shape Formulation EXAMPLE 2A 2B 2C 2D 2E 2FMaterial % by Weight Sucralose 0.71 0.67 0.65 0.63 0.62 0.62 Peppermint1.93 1.83 1.76 1.72 1.68 1.55 Flavor Citric Acid 0.00 0.00 0.00 0.000.00 1.08 Anhydrous Sodium 0.00 0.00 0.00 0.00 0.00 1.55 BicarbonateAPAP Granular 88.51 83.91 80.66 78.75 76.93 77.40 Polyglykol 8.85 8.398.07 7.88 7.69 7.74 4000 Polyethylene 0.00 1.01 4.84 7.09 9.23 6.19Oxide Tapioca 0.00 4.20 4.03 3.94 3.85 3.87 Maltodextrin Total 100.00100.00 100.00 100.00 100.00 100.00

Example 3 Preparation of Tablet Shapes Containing Hot-Melt CoatedIbuprofen Part 1: Preparation of Coated Ibuprofen

2000 kg of ibuprofen crystals (particle size grade 110 μm) is chargedinto a Glatt fluid bed GPCG 5/9 coater equipped with a Wurster Insert.Glyceryl palmitostearate, commercially available from the GattefosseCorporation (St-Priest, France) as Precirol ATO is placed into asuitable stainless steel container and melted at 70 degrees Celsiusuntil it is completely melted. The melted material is then sprayed ontothe ibuprofen at a spray rate of approximately 20 g/minute whilefluidizing at a product temperature of approximately 30 degrees Celsius.The coated ibuprofen is then discharged from the unit.

Part 2: Preparation of Tablet Shape:

The tablet shapes of Table 3 are prepared as follows. The sucralose,peppermint flavor, and tapioca maltodextrin are manually passed througha 50 mesh screen. The coated ibuprofen, polyethylene glycol, andpolyethylene oxide are added to the above mixture in a plastic bottle,mixed end-over end for approximately three minutes, and then discharged.The blend is then individually dosed into a simulated capsule-likemedicament (“caplet”) die utilizing 624 mg of the blend per tablet. Thetablet shapes are then heated using convection heat to fuse thegranulation into a unified tablet.

TABLE 3 APAP 500 mg Tablet Shape Formulation Material G/Batch mg/tabWeight % Sucralose 0.84 3.0 0.84 Peppermint Flavor 1.96 7.0 1.96Hot-Melt Coated Ibuprofen¹ (70%) 79.87 285.70 79.87 Polyglykol 4000(Polyethylene Glycol) 1.96 7.0 1.96 Polyethylene Oxide (Grade WSR 303)9.78 35.0 9.78 Tapioca Maltodextrin (N-Zorbit M) 5.59 20.0 5.59 TOTAL100.0 357.70 100.0 ¹Commercially available from Virginia Dare inBrooklyn, NY 2: Equivalent to 200 mg Ibuprofen (per tablet) 3:Commercially available from Clariant PF in Rothausstr, Switzerland 4:Commercially available from the DOW Corporation in Midland, MI 5:Commercially available from National Starch in Bridgewater, NJ

Example 4 Water Permeation Time

The water permeation test was performed utilizing the Texture AnalyzerTAXT Plus, commercially available from Texture Technologies inScarsdale, N.Y., equipped with a TA-55 probe. The following tablets wereanalyzed: (i) a tablet of Example 1; (ii) a Motrin® 100 mg Chewabletablet, commercially available from McNeil Consumer Healthcare (FortWashington, Pa.); and (iii) Tylenol® 160 mg Meltaways, commerciallyavailable from McNeil Consumer Healthcare. The results are depicted inFIG. 15.

As is shown in FIG. 15, the tablet of Example 1 disintegratedimmediately following the addition of the water as indicated by theprobe distance, which increased to almost 2 mm within 10 secondsfollowing immersion in water. The two reference chewable tablets did notdisintegrate until after 170 seconds following immersion, when the probedistance increased to more than 1 mm. These results indicate that uponaddition of water, the tablet of Example 1 disintegrated at a fasterrate than the conventional chewable tablets.

Example 5 In Vitro Disintegration Time

The tablets of the present invention were analyzed utilizing thedisintegration apparatus described in the United States Pharmacopeia(USP 33-NF 28), Section <701>, wherein the apparatus was equipped with a10 mesh screen. The tablet formulations from Example 2 were used, havingvarious levels of the hydrocolloid polyethylene oxide, in order toobserve the effect of this hydrocolloid on the disintegration time. InExample 2F, the presence of the effervescent couple citric acid andsodium bicarbonate were added to the blend in order to evaluate itseffect on disintegration. The commercially available fast disintegratingtablets Nurofen Meltlets and Risperdal M-Tabs were also tested. Theresults are shown in Table 4. The results indicate that while they brokedown into a semisolid mass in the water, the samples with higher levelsof hydrocolloid were remained as a semi solid mass and did not fullypass through the screen for over well over 60 seconds.

TABLE 4 Disintegration Time of Tablets with Varying Levels ofHydrocolloid % w/w of Sample Hydrocolloid Disintegration Result inSeconds Example 2A 0.0 Disintegrated in 12 seconds Example 2B 1.0Disintegrated in 20 seconds Example 2C 4.8 Disintegrated in 300 secondsExample 2D 7.1 Intact at 300 seconds Example 2E 9.2 Intact at 300seconds Example 2F 6.2 Disintegrated in 65 seconds Nurofen Meltlets^(a)NA Disintegrated in 75 seconds Risperdal M-Tab^(b) NA Disintegrated in 2seconds Children's Tylenol NA Disintegrated in 180 seconds Meltaways^(c)^(a)Nurofen Meltlets (Commercially available from Crookes Healthcare, inNottingham, UK) ^(b)Risperdal M-Tab Orally Disintegrating Tablet(Commercially available from Janssen Corporation, in New Brunswick, NJ)^(c)Children's Tylenol Meltaways (Commercially available from McNeilConsumer Healthcare in Fort Washington, PA)

Example 6 Preparation of Tablet Shapes and Resulting Tablets ContainingAcetaminophen and a Hydrated Salt

The tablet shapes of Table 5 are prepared as follows. The sucralose,peppermint flavor and tapioca maltodextrin are manually passed through a50 mesh screen. The acetaminophen (APAP) granular, sodium hydrogenphosphate hydrate are added to the above mixture in a plastic bottle,mixed end-over end for approximately three minutes, and then discharged.The blend is then individually dosed into a simulated capsule-likemedicament (“caplet”) die utilizing 624 mg of the blend per tablet. Thedie is constructed of a non-conductive plastic and the forming tools arein operably associated with the electrodes within an Rf unit. The tabletshapes are then heated and activated utilizing Rf energy for 2 to 5seconds to sinter the powder blend into a unified tablet. The tablet isthen ejected from the die platen.

TABLE 5 APAP 500 mg Tablet Shape Formulation Material G/Batch mg/tabWeight % Sucralose 0.66 4.0 0.66 Peppermint Flavor¹ 1.66 10.0 1.66 APAPGranular² (uncoated 82.78 500.0 82.78 granulation) Tapioca Maltodextrin(N-Zorbit M³) 4.97 30.0 4.97 Sodium Hydrogen Phosphate Hydrate⁴ 9.9360.0 9.93 TOTAL 100.0 604.0 100.0 ¹Commercially available from VirginiaDare in Brooklyn, NY ²Commercially available from MallinckrodtCorporation in Hazelwood, MO ³Commercially available from Clariant PF inRothausstr, Switzerland ⁴Commercially available from the AroseCorporation in Bellmawr, NJ ³Commercially available from National Starchin Bridgewater, NJ

Example 7 Preparation of Tablet Shapes and Resulting Tablets ContainingAcetaminophen and a Meltable Binder

The tablet shapes and resulting tablets of Table 6 are prepared as abovein Example 6.

TABLE 6 APAP 500 mg Tablet Shape Formulation Material G/Batch mg/tabWeight % Sucralose 0.68 4.0 0.68 Peppermint Flavor 1.71 10.0 1.71 APAPGranular (uncoated granulation) 85.6 500.0 85.6 Tapioca Maltodextrin(N-Zorbit M) 5.14 30.0 5.14 Polyethylene Oxide NF² 2.57 15.0 2.57Carnauba wax ¹ 4.28 25.0 4.28 TOTAL 100.0 584.0 100.0 ¹ Microcare 350commercially available from Micro Powders Inc. (Tarrytown, NY) ²PolyoxWSR 303 commercially available from Dow Corporation (Midland, MI)

It is understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the claims.

What is claimed is:
 1. A tablet comprising one or more pharmaceuticallyactive agent(s), one or more thickeners, and one or more binder(s),wherein said tablet comprises at least 200 mg of said pharmaceuticallyactive agent(s) and said tablet has been fused with said binder(s) suchthat said tablet (i) has a water permeation time of less than 60 secondsand (ii) has an in vitro disintegration time of greater than 60 seconds.2. The tablet of claim 1, wherein said tablet has a water permeationtime of less than 30 seconds.
 3. The tablet of claim 1, wherein saidtablet has an in vitro disintegration time of greater than 180 seconds.4. The tablet of claim 1, wherein said tablet comprises at least 5%, byweight, of said binder(s).
 5. The tablet of claim 1, wherein saidbinder(s) is a RF-meltable binder having a melting point of from about40° C. to about 140° C.
 6. The tablet of claim 1, wherein said tabletcomprises the binder polyethylene glycol.
 7. The tablet of claim 1,wherein said binder is water-activating binding material.
 8. The tabletof claim 1, wherein said tablet comprises at least 50%, by weight, ofsaid pharmaceutically active agent(s).
 9. The tablet of claim 1, whereinsaid tablet comprises a pharmaceutically active agent is selected fromibuprofen, acetaminophen, antacids, a vitamin, metformin, andpharmaceutically acceptable salts thereof.
 10. The tablet of claim 1,wherein said tablet comprises the thickener polyethylene oxide.
 11. Thetablet of claim 1, wherein said tablet comprises less than ten percent,by weight, of carbohydrates.
 12. A method of administering one or morepharmaceutically active agent(s), said method comprising placing a solidtablet comprising said pharmaceutically active agent(s) into the mouthfollowed by swallowing a liquid, wherein said tablet comprises at least200 mg of said pharmaceutically active agent(s) and said tablet (i) hasa water permeation time of less than 60 seconds and (ii) has an in vitrodisintegration time of greater than 60 seconds.
 13. The method of claim12, wherein said tablet comprises at least 50%, by weight, of saidpharmaceutically active agent(s).
 14. The method of claim 12, whereinsaid tablet comprises at least 325 mg of the pharmaceutically activeagent acetaminophen.
 15. The method of claim 12, wherein said tabletfurther comprises a thickener.
 16. A process for making a tabletcomprising one or more pharmaceutically active agent(s), one or morethickeners, and one or more binder(s), said method comprising the stepsof: (a) forming a tablet shape a powder blend comprising saidpharmaceutically active agent(s) and a binder; and (b) applying energyto said tablet shape for a sufficient period of time to activate saidbinder(s) within said tablet shape to fuse said tablet shape into saidtablet, such that said tablet (i) has a water permeation time of lessthan 60 seconds and (ii) has an in vitro disintegration time of greaterthan 60 seconds.
 17. The process of claim 16, wherein said binder is ameltable material having a melting point of from about 40° C. to about140° C. and said tablet shape is exposed to said energy for a sufficientperiod of time to melt or soften said meltable material.
 18. The processof claim 16, wherein said binder is an RF-meltable binder and saidtablet shape is exposed to RF energy for a sufficient period of time tomelt or soften said meltable material.
 19. The process of claim 16,wherein said binder is water-activating binding material, said powderblend further comprises a water-containing material, and said tabletshape is exposed to said energy for a sufficient period of time to heatthe water-containing material above its dehydration temperature.
 20. Theprocess of claim 16, wherein said powder blend is compressed in a dieplaten and said energy is applied to said tablet shape within said dieplaten.
 21. The process of claim 16, wherein said powder blend comprisesparticles comprising said pharmaceutically active agent wherein saidparticle is coated with said binder.
 22. The process of claim 1, whereinthe surface of said tablet is further exposed to infrared energy whereinthe majority of the wavelength of said infrared energy from about 0.5 toabout 5 micrometers.